Chiral oligomeric pentenoate amides as bio-oligomer mimetics

Patent metadata

Field	Value
Publication number	US-9963481-B2
Application number	US-201214343426-A
Country	US
Kind code	B2
Filing date	Sep 7, 2012
Priority date	Sep 7, 2011
Publication date	May 8, 2018
Grant date	May 8, 2018

Abstract

Chiral oligomeric pentenoate amides are bio-oligomer mimetics possessing a high degree of conformation rigidity. Conformational rigidity is desirable in the design of molecules with high affinities for biological receptors and enzymes. Libraries of such oligomeric mimetics, such as of chiral oligomeric pentenoate amides can be used to probe biological systems. The present invention provides a method for preparation of chiral oligomeric pentanoate amides comprising conversion of a chiral oxazolidinone (4)

to a chiral monomer of formula (1)

which can be oligomerized to a chiral compound of formula (12)

and so forth.

First claim

What is claimed:

1. A method of synthesizing a chiral monomer of formula (1)

comprising:
N-acylating a chiral oxazolidinone of formula (4)

wherein Bn is benzyl, and the compound of formula (4) is a chiral form,
by contacting (4) with propionic acid in the presence of ethyl chloroformate, N-methylmorpholine, and LiCl in THF, to provide a chiral N-acyloxazolidinone of formula (5)

then, reacting the chiral N-acyloxazolidinone of formula (5) and an α-substituted, α,β-unsaturated aldehyde of formula (6)

via a magnesium halide catalyzed stereoselective reaction comprising contacting (5) and (6) with MgBr 2 and NaSbF 6 in ethyl acetate, followed by trimethylsilylchloride to yield a chiral silylated allylic alcohol product of formula (7)

wherein TMS is trimethylsilyl, then,
reacting the chiral silylated allylic alcohol (7) with NbCl 5 in dioxane solvent to yield a stereodefined allylic chloride of formula (8)

by a stereoselective halogenation reaction that proceeds via stereoselective allylic transposition; then,
hydrolyzing the oxazolidine group to produce a chiral monomer of formula (1)

2. The method of claim 1 further comprising a method wherein two monomers of formula (1) are oligomerized,
comprising contacting the compound of formula (1) and secondary amine pyrrolidine (9) in the presence of ethyl chloroformate and N-methylmorpholine in THF to provide a chiral chloroamide of formula (10)

then, coupling the chloroamide of formula (10) and primary amine benzylamine in the presence of triethylamine in THF to provide a chiral allylic amine of formula (11)

wherein Bn is benzyl, then,
coupling the compound of formula (11) and the compound of formula (1), in the presence of ethyl chloroformate and N-methylmorpholine in THF to provide the chiral oligomeric pentenoic amide (COPA) of formula (12)

3. A chiral oligomeric pentenoic amide of formula:

wherein F5M is a Fluorescein-5-maleimide adduct.

Assignees

• Micalizio Glenn C
• Kodadek Thomas
• Sarkar Mohosin
• Scripps Research Inst

Inventors

• Micalizio Glenn C
• Kodadek Thomas
• Sarkar Mohosin

Classifications

• C07B2200/07

  Optical isomers · CPC title

• C07C57/64

  Acyl halides · CPC title

• G01N2800/7028

  Cancer · CPC title

• A61K38/06

  Tripeptides · CPC title

• C07D405/10

  linked by a carbon chain containing aromatic rings · CPC title